Efficacy and safety of glucocorticoids in the treatment of COVID-19: a systematic review and meta-analysis of RCTs

In the realm of acute respiratory infections, coronavirus disease-19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a global public health challenge. The application of corticosteroids (CSs) in COVID-19 remains a contentious topic among researchers. Accordingly, our team performed a comprehensive meta-analysis of randomized controlled trials (RCTs) to meticulously evaluate the safety and efficacy of CSs in hospitalized COVID-19 patients. To explore efficacy of CSs in the treatment of COVID-19 patients, we meticulously screened RCTs across key databases, including PubMed, Web of Science, Embase, Cochrane Library, ClinicalTrials.gov, as well as China's CNKI and Wanfang Data. We focused on assessing the 28 days mortality rates. We evaluated the data heterogeneity using the Chi-square test and I2 values, setting significance at 0.1 and 50%. Data from 21 RCTs involving 5721 participants were analyzed. The analysis did not demonstrate a significant association between CSs intervention and the 28 days mortality risk in hospitalized COVID-19 patients (relative risk [RR] = 0.93; 95% confidence interval [95% CI]: 0.84–1.03; P = 0.15). However, subgroup analysis revealed a significant reduction in 28 days mortality among patients with moderate-to-severe COVID-19 (RR at 0.85; 95% CI: 0.76–0.95; P = 0.004). Specifically, short-term CS administration (≤ 3 days) was associated with a substantial improvement in clinical outcomes (RR = 0.24; 95% CI: 0.09–0.63; P = 0.004), as was longer-term use (≥ 8 days) (RR = 0.88; 95% CI: 0.77–0.99; P = 0.04). Additionally, in patients with moderate-to-severe COVID-19, the administration of dexamethasone increased the number of 28 days ventilator-free days (Mean Difference = 1.92; 95% CI: 0.44–3.40; P = 0.01). Methylprednisolone also demonstrated significant benefits in improving clinical outcomes (RR = 0.24; 95% CI: 0.09–0.63; P = 0.004). Our meta-analysis demonstrated that although there is no significant difference in 28 days mortality rates among hospitalized COVID-19 patients, the use of CSs may be beneficial in improving clinical outcomes in moderate or severe COVID-19 patients. There was no significant increase in the occurrence of adverse events associated with the use of CSs. Our meta-analysis provides evidence that while CSs may not be suitable for all COVID-19 patients, they could be effective and safe in severely ill COVID-19 patients. Consequently, it is recommended to administer CSs for personalized treatments in COVID-19 cases to improve the clinical outcomes while minimizing adverse events. Supplementary Information The online version contains supplementary material available at 10.1007/s10238-024-01405-0.


Introduction
The COVID-19, caused by SARS-CoV-2, has become the most severe global public health emergency and greatly impacted the world since its outbreak at the end of 2019 [1].The COVID-19 infection is characterized by increased mobility and high mortality rate, especially among the elderly patients with underlying diseases [2].By December 6, 2023, this pandemic has resulted in over 772 million cases and 6.98 million fatalities worldwide, presenting unprecedented challenges to human health and healthcare systems [3].
For individuals with confirmed COVID-19, novel targeted therapeutics for COVID-19 treatment still remain limited.To date, the supportive care remains the primary medical interventions for COVID-19 cases, and medications often prove ineffective and may carry the risk of toxicity, particularly when used in combination [4].It is noteworthy that the World Health Organization recommended the application of CSs in severe and critical COVID-19 patients [5].Initial recommendations from the Infectious Diseases Society of America in September 2022 were against the routine use of CSs for COVID-19, unless there were critically ill COVID-19 hospitalized patients or other reasons, such as asthma, or refractory shock [6].However, the efficacy and safety of CSs in COVID-19 patients have been a debate within the medical community [7].On the one hand, several studies underscore the potential therapeutic benefits of CSs administration; on the other hand, there is a growing body of literature highlighting adverse outcomes associated with CSs.For example, Li and colleagues found the use of CSs in COVID-19 patients is associated with prolonged viral RNA shedding, raising concerns about potential adverse effects [8,9].In addition, there were several studies that have shown either no benefit or an increased mortality in different subgroup of cases [10][11][12][13].This ongoing controversy highlights the critical need for continued and comprehensive systematic review and meta-analysis to provide more evidence for the efficacy of CSs therapy in COVID-19 cases.
Considering all factors mentioned above, we conducted a systematic review and meta-analysis to assess the safety and efficacy of CSs therapy in hospitalized COVID-19 patients, juxtaposed with non-steroid treated groups and cohorts receiving different steroid dosages.Moreover, our analysis further analyzed different CSs subgroups in terms of disease severity, dosage, the specific type of CSs employed, and the duration of treatment.Our aim is to offer more therapeutic options to physicians and the medical community.

Databases and search strategy
In accordance with the rigorous standards set by the PRISMA declaration, our study was duly registered on the PROSPERO platform (CRD42023486275).Our methodological approach entailed an extensive and strategic literature search across a suite of databases including PubMed, Web of Science, Embase, Cochrane Library, ClinicalTrials.gov,CNKI, and Wanfang Data.We designed a comprehensive search algorithm, blending both MeSH terms and free-text terms in a Boolean framework.The MeSH terms are listed as follows: COVID-19, glucocorticoid, dexamethasone, prednisolone, and prednisone.The freetext terms are SARS-CoV-2, 2019 Novel Coronavirus, methylfluorprednisolone, hexadecadrol, and so on (see Table 1 of Supplemental Material file online for more details regarding the search strategies).The search string was crafted to capture a wide range of literature related to COVID-19 and CSs therapy, leading to a comprehensive retrieval of 5757 articles, including one identified through manual search, up to the cutoff date of November 21, 2023.

Eligibility criteria
This investigation entailed a systematic appraisal of RCTs, following stringent criteria encompassing participant characteristics, intervention strategies, comparison groups, outcome measures, and study designs.Inclusion was limited to patients aged 18 and above, diagnosed with COVID-19 according to established clinical guidelines [14].The interventions under review were various CSs therapies, set against control groups receiving either alternate dosages of CSs, standard supportive care, or placebo [14].
Study selection was undertaken independently by two researchers (Xiangrong Ye and Ye Li), who diligently reviewed titles and abstracts for relevance.Disparities in selection were resolved through joint discussions or by consulting a third arbitrator (Feng Luo).For articles lacking complete data, efforts were made to obtain additional information from the study's corresponding authors.The Cochrane Risk of Bias Tool 2.0 was utilized to assess the methodological robustness and potential bias of the studies included [15].

Data collection process
The primary outcomes of this investigation were the 28 days mortality rate.The secondary outcomes evaluated included the duration of hospitalization, the number of days free from mechanical ventilation within the first 28 days, rates of ICU transfer, and the 60 days mortality rate.The study also analyzed adverse events, specifically focusing on secondary infections such as bacteremia and fungal infections, as well as significant adverse events categorized as Grade 3-4.Patients requiring prolonged CSs or immunosuppressive treatment for chronic ailments were systematically excluded.Data collation and extraction were executed independently by two distinct groups, ensuring the integrity and precision of the data collection process.

Assessment of risk of bias and quality of evidence
In conducting this study, evaluators Ye and Li independently applied the Cochrane Risk of Bias Tool for a detailed and systematic assessment of the randomized controlled trials under review.This comprehensive evaluation targeted seven critical aspects: (1) the methodology of random sequence generation, (2) the integrity of allocation concealment, (3) the effectiveness of blinding for participants and personnel, (4) the impartiality of outcome assessment blinding, (5) the completeness and reliability of outcome data, (6) the presence of selective reporting biases, and (7) the potential influence of other bias sources.Each domain was meticulously appraised, classified into categories of 'low,' 'unclear,' or 'high' risk of bias, with the overarching bias risk for each trial being determined by the highest risk level noted across these domains.

Data analysis
For the statistical analysis, the Review Manager (RevMan) version 5.3 was used, a tool by the Cochrane Collaboration.Heterogeneity among study results was assessed with Chisquare and I 2 tests, applying thresholds of 0.1 and 50%, respectively, under a random-effects model framework.Preference was given to the I 2 test results in cases of inconsistency.The Mantel-Haenszel method was utilized for binary data synthesis, deriving pooled RR along with their 95% CIs.Continuous outcomes were analyzed using the inverse variance approach, with mean differences (MDs) and corresponding 95% CIs as the metrics.In situations where only medians and interquartile ranges were reported, the mean-variance estimation method was employed for mean and standard deviation estimations [16].Publication bias was probed using the funnel plots, Egger's test, and Begg's test [17].

Risk of bias and quality of evidence
Within the analyzed cohort of studies, fourteen were adjudged to have a low risk of bias.Six studies were categorized as having unclear risk, primarily due to ambiguities in the implementation of blinding, measurement of outcomes, and descriptions of allocation concealment.One study was identified to present a high risk of bias, specifically attributed to inadequacies in allocation concealment (Figs. 2 and  3).

Primary outcomes: 28 days mortality
Across 20 studies [19, 23, 28-32, 34, 35, 37, 39], involving 4898 subjects, the 28 days mortality rates were analyzed.Within the CSs-treated cohort, the mortality rate stood at 19.4%, whereas the control group exhibited a rate of 20.2%.The computed RR was 0.93 (95% CI: 0.84-1.03;P = 0.15), suggesting there is no statistically significant correlation between CSs intervention and the control group with regard to the 28 days mortality rate among hospitalized COVID-19 patients (Fig. 4).Thus, CSs treatment did not confer a reduced risk of 28 days mortality.The heterogeneity assessment, conducted using Chi-square and I 2 tests, indicated the absence of significant heterogeneity (30.19 and 37%, respectively).

Discussion
In contrast with previously published meta-analyses, our study presents several distinct advantages.It incorporates an expanded cohort of 21 RCTs, including cases of moderate or severe COVID-19.In addition, our research features a larger sample size, which enhances the quality of this study.In our findings, the benefits of CSs application were less evident in the general hospitalized patient population.Nevertheless, our findings show that CSs significantly reduce the 28 days mortality rate and increase the VFD over a 20 days period in COVID-19 patients with moderate or severe ARDS, which is possibly due to variations in disease severity and the diversity of CSs dosages administered to COVID-19 patients.
Focusing on COVID-19, the pharmacodynamics of hydrocortisone and dexamethasone and their impact on COVID-19 patients have been highlighted in recent WHOsponsored trials and meta-analyses [40].Our findings are in line with the RECOVERY trial, which demonstrated the reduction in 28 days mortality for patients with hypoxia or mechanical ventilation when treated with dexamethasone [41].
Based on results of our analysis, the use of CSs did not increase the risk of serious adverse events, secondary infections, bacteremia, and fungal infections in COVID-19 patients with ARDS.It is notable that, in severe COVID-19 cases, CSs application was associated with a reduced risk of fungal infections.This may be attributed to the potent anti-inflammatory effects of CSs, which can improve clinical outcomes [42].Critically ill COVID-19 patients may benefit even more from higher dosage of CSs [43].Furthermore, some studies suggest potential benefits of inhaled CSs in preventing disease deterioration and secondary organ damage in patients with COVID-19, which could be a new therapeutic option [44,45].
In the present study, CSs treatment was not found to improve the disease prognosis in certain subgroups, such as the intermediate treatment duration (4-7 days) of CSs and the combination therapy of dexamethasone and methylprednisolone and intermediate duration (4-7 days) of CSs treatment, underscoring the necessity for further targeted clinical research [2].As such, the current body of evidence does not support a universal application of CSs therapy among all hospitalized COVID-19 patients, and further stratified clinical research is required to demonstrate its efficacy [5].This underscores the critical necessity for careful consideration in the clinical decision-making regarding the use of CSs as the clinical application of CSs is fraught with complexity.Inappropriate administration of CSs is associated with heightened risks of infection, osteoporosis, hyperglycemia, and bleeding, potentially worsening the patient's condition [46,47].
Accordingly, identifying the optimal timing for CSs therapy is crucial.Our subgroup analysis demonstrates that durations of CSs treatment (≤ 3 days or ≥ 8 days) Variations in recommended treatment durations for CSs might be attributed to the distinct metabolic pathways activated by different CSs, such as methylprednisolone and dexamethasone.They exert potent anti-inflammatory effects by binding with glucocorticoid response elements, modulating transcription factors, and inf luencing secondary messenger pathways [50].This underscores the significance of selecting the appropriate CSs type for COVID-19 treatment [51], as the choice of CSs for treating COVID-19 remains an area of ongoing exploration.New clinical studies are required to explore the specific populations that may benefit from CSs, as well as to refine the timing and duration of CSs application, with the aim of optimizing the benefits of CSs while minimizing their potential harm.

Limitations
We acknowledge several inherent limitations.Firstly, considering the methodology of systematic reviews and meta-analyses, the issue of heterogeneity is inevitable, exacerbated by the diversity in patient demographics, therapeutic approaches, and the types of CSs administered.The second limitation arises from the inadequate reporting of adverse events in certain studies we analyzed, which constrains the conclusiveness of subgroup analysis in this context.Moreover, the short follow-up periods in the included RCTs limit the understanding of long-term adverse effects of CSs administered at varying doses and durations.This necessitates further research through observational studies or additional randomized trials to thoroughly understand the prolonged implications of CSs therapy in such cases.there was no significant difference in 28 days mortality rates among hospitalized COVID-19 patients, our results show that CSs may be beneficial in improving clinical outcomes by choosing appropriate duration and type of application specially for COVID-19 patients with moderate or severe ARDS.Additionally, there was no significant increase in the incidence of adverse events associated with the use of CSs.It should be noted that our research has inherent limitations and bias is inevitable.Consequently, it is recommended to administer CSs for an personalized duration in moderate or severe COVID-19 cases to improve the clinical outcomes while minimizing adverse events.Our meta-analysis provides evidence that CSs are not suitable for all COVID-19 patients, but they could be effective and safe in severely ill COVID-19 patients.

Fig. 1
Fig. 1 PRISMA flow diagram for search

Fig. 4 Fig. 5 Fig. 6
Fig. 4 Effect of corticosteroids on mortality at 28 days among hospitalized patients

Fig. 7
Fig. 7 Effect of corticosteroids on 28 days ventilator-free days among hospitalized patients

Fig. 8
Fig. 8 Adverse events of corticosteroids among hospitalized patients

Table 3
Subgroup analysis of the variables influencing factors with clinical outcomes of COVID-19 RR: relative risk; MD: mean difference; CI: confidence interval; *: have statistical significance